Since the identification of HCV in 1989, it is today estimated that 180 million individuals are infected worldwide of which 130 million are chronic HCV carriers at risk of developing liver cirrhosis and/or liver cancer. See Kantzanou, M., et al. (2003) Viral escape and T cell exhaustion in hepatitis C virus infection analysed using Class I peptide tetramer, Immunol Lett 85:165-71, which is hereby incorporated by reference in its entirety. Being a small enveloped RNA virus, HCV is one of the most persistent viruses in humans. Spontaneous resolution of HCV infection occurs in a minority of infected individuals. See Alter, H. 2006. Viral hepatitis. Hepatology 43:S230-4, which is hereby incorporated by reference in its entirety. Considering the steady increase of reported incidence in Europe and the fact that current interferon therapy is only 50-60% effective, a reduction of HCV prevalence is not anticipated in the near future. Several promising HCV specific inhibitors designed to impair the protease/polymerase activity of HCV non-structural proteins (NS) 3-5 are currently in clinical evaluation. See Kronenberger, B., and S. Zeuzem, (2009) Current and future treatment options for HCV. Ann Hepatol 8:103-12, which is hereby incorporated by reference in its entirety.
Based on analysis of individuals who have resolved HCV infection, it appears that a successful immunity requires T cell control and clearance. Bowen, D. G., and C. M. Walker, (2005) Adaptive immune responses in acute and chronic hepatitis C virus infection, Nature 436:946-52. It is now known that CD4+ and CD8+ lymphocyte activation early in the infection is strongly associated with eradication of HCV infection, and an early development of polyfunctional T cells may further predict a spontaneous resolution of HCV infection. Failure to sustain virus-specific CD8+ lymphocytes may, on the other hand, contribute to persistence of the virus. Lechner, F., N. H. Gruener, S. Urbani, J. Uggeri, T. Santantonio, A. R. Kammer, A. Cerny, R. Phillips, C. Ferrari, G. R. Pape, and P. Klenerman. (2000) CD8+ T lymphocyte responses are induced during acute hepatitis C virus infection but are not sustained, Eur J Immunol 30:2479-87, which is hereby incorporated by reference in its entirety. Features in HCV-specific T lymphocytes, such as, functional exhaustion, developmental arrest, tolerance induction, impairment in proliferative capacity and effector function are often observed in the chronic phase of infection. Some believe these events are a consequence of continued antigen stimulation, or a viral factor leading to Antigen Presentation Cell (APC) suppression, but considerable uncertainty still remains. Nevertheless, it appears that dysfunctional effector T cells ineffectively control the infection and the persistence of the virus leads to long-term liver damage in the host.
Many studies have investigated HCV infection and the host immune response, however, very often these studies are conducted in an allogeneic setting by assessing the magnitude of lymphocytic activity in mixed lymphocyte reactions. Bona fide HCV antiviral lymphocytic activations have been examined in very few studies. The limited number of existing human HCV T-cell clones could be one explanation, however, the relatively short lifespan of primary T cell lines is surely a contributing factor. The need for a better understanding of how HCV and HCV-infected cells are recognized and responded to by the immune system is manifest.